Medicine and Health Sciences Commons^™

The Role Of Mucin-Educated Platelet Activation In Tumor Invasiveness: An Unfolding Concern In The Realm Of Cancer Biology, Akbar Shoukat Ali, Arzoo Ajaz

Department of Obstetrics & Gynaecology

Metastasis is a complex and well-coordinated phenotypic transformation of cancer cells governed by aberrant genetic and molecular pathways. It has been approved as the most consistent cause of cancer death. With emerging insight into the genomics, transcriptomics and proteomics, progress has been made and reasonably large number of molecular pathways of metastasis has been forwarded, but our understanding of precise underlying molecular mechanisms remains largely scarce. It has been well-known for around a decade and more that platelets are intriguingly contributing to the cancer metastasis. However, it is only recently that cancer cells can activate platelets have started to become …

Alcohol And Cancer Stem Cells, Mei Xu, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced …

The Role Of Talin2 In Breast Cancer Tumorigenesis And Metastasis, Liqing Li, Xiang Li, Lei Qi, Piotr G. Rychahou, Naser Jafari, Cai Huang

Markey Cancer Center Faculty Publications

Recent studies show that talin2 has a higher affinity to β-integrin tails and is indispensable for traction force generation and cell invasion. However, its roles in cell migration, cancer cell metastasis and tumorigenesis remain to be determined. Here, we used MDA-MB-231 human breast cancer cells as a model to define the roles of talin2 in cell migration, invasion, metastasis and tumorigenesis. We show here that talin2 knockdown (KD) inhibited cell migration and focal adhesion dynamics, a key step in cell migration, and that talin2 knockout (KO) inhibited cell invasion and traction force generation, the latter is crucial for cell invasion. …

Robustness Of A Newly Proposed Risk Schema For Lymphatic Dissemination In Endometrioid Endometrial Cancer, Danielle M. Greer, Jessica J.F. Kram, Callie M. Cox Bauer, Scott A. Kamelle

Journal of Patient-Centered Research and Reviews

Background: Surgical management for endometrioid endometrial cancer (EEC) includes complete lymph node dissection for all patients at risk of lymphatic dissemination. The standard risk schema, defined by Mayo Clinic, identifies low-risk patients as those with grade 1/2 EEC, myometrial invasion (MI) ≤ 50%, and tumor diameter (TD) ≤ 2 cm. We recently proposed (and published) a risk schema containing modified forms of grade, MI and TD that suggests a significant decrease in false-negative rate and need for lymphadenectomy in low-risk women.

Purpose: Evaluate robustness of our proposed schema for lymphatic dissemination risk stratification in a subsequent EEC patient cohort.

Methods: …

Angptl4 Promotes The Progression Of Cutaneous Melanoma To Brain Metastasis., Sivan Izraely, Shlomit Ben-Menachem, Orit Sagi-Assif, Tsipi Meshel, Diego M Marzese, Shuichi Ohe, Inna Zubrilov, Metsada Pasmanik-Chor, Dave S B Hoon, Isaac P Witz

Articles, Abstracts, and Reports

In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such metastases. The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis. We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas …

Multimodality Therapy Improves Survival In Intramedullary Spinal Cord Metastasis Of Lung Primary, Hayder Saeed, Reema Patel, Jigisha Thakkar, Lames Hamoodi, Li Chen, John L. Villano

Internal Medicine Faculty Publications

Background: Most metastatic spinal cord lesions are located either in the intradural, extramedullary, or in the epidural compartments. Intramedullary spinal cord metastasis (ISCM) is a rare central nervous system spread of cancer. The aim of this report was to evaluate ISCM in the published literature.

Methods: A literature review of PubMed from 1960 to 2016 was undertaken for the publications having demographic, clinical, histological, and outcome data.

Results: A total of 59 relevant papers were identified, showing 128 cases of intramedullary metastasis from lung cancer. The incidence of lung cancer as the primary malignancy with intramedullary metastasis was 56%. The …

Pharmacologic Or Genetic Targeting Of Glutamine Synthetase Skews Macrophages Toward An M1-Like Phenotype And Inhibits Tumor Metastasis., Erika M. Palmieri, Alessio Menga, Rosa Martín-Pérez, Annamaria Quinto, Carla Riera-Domingo, Giacoma De Tullio, D Craig Hooper, Wouter H. Lamers, Bart Ghesquière, Daniel W. Mcvicar, Attilio Guarini, Massimiliano Mazzone, Alessandra Castegna

Department of Cancer Biology Faculty Papers

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial …

Effects Of Stroma On Er+ Breast Cancer Cell Metastasis, Shipeng Xu, Luis Solorio, Sarah Calve

The Summer Undergraduate Research Fellowship (SURF) Symposium

Breast cancer is one of the most wide-spread diseases among women in America. If the cancer is local, it is easily controlled by surgical resection. However, if the cancer cells metastasize, patient survival is significantly reduced. 70% of breast cancers can be targeted through estrogen receptors (ER) on the membrane, with compounds such as tamoxifen. However, tamoxifen shows unreliable outcomes on different patients and it is believed that the ineffectiveness of tamoxifen is related to the epithetical-mesenchymal transition (EMT) of cancer cells. To address this problem, we are designing a system that stimulates metastasis activation with the aim of incorporating …

The Role Of The Epithelial-To-Mesenchymal Transition (Emt) In Lung Cancer Progression, David H. Peng

Dissertations & Theses (Open Access)

Lung cancer is the leading cause of cancer-related deaths due to conventional therapy resistance and metastatic disease, therefore understanding the mechanisms governing these biological functions is vital for improving patient survival. Approximately 30% of patients with the adenocarcinoma histologic subset of lung cancer possess an activating KRAS mutation, characterized by a lack of response to chemotherapies with a poor overall 5-year survival rate. Despite the mutational frequency, KRAS remains a challenge to pharmacologically inhibit and current drugs undergoing clinical trials that target specific downstream effector proteins of KRAS, such as MEK inhibitors, have failed to produce significant clinical benefits. Previous …

Prostate Cancer In African American Men, Chinwe Egwudo

Nursing Student Class Projects (Formerly MSN)

Prostate cancer, a malignancy with racial disparity, affects African American men more than Caucasians or any other race.

Primary Lung Carcinoid Metastatic To The Breast, Marianna Zagurovskaya, Karen Tran-Harding, Richard Gibbs

Radiology Faculty Publications

Lung carcinoid tumors account for approximately 2% of lung cancers, with 10% of the tumors represented by the atypical type. While atypical carcinoids are metastatic to intrathoracic lymph nodes in approximately half of the cases on the initial presentation, distant metastases are seen in only 20% of the patients and are found most frequently in bones, liver, adrenal glands, and brain. We present a case of an unusual metastatic disease to the breast in 51-year-old female who developed a new breast mass 2 years after left lower lobectomy due to atypical carcinoid tumor. Atypical pulmonary carcinoid metastases to the breast …

The Effects Of Lipocalin 2 On Lung Metastasis Of Colorectal And Other Cancers, Lauren Strzyzewski

Senior Theses

Lipocalin 2 (Lcn2) is a member of the lipocalin family of siderophore-binding molecules that can mediate iron trafficking. It acts during the innate immune response and has been implicated in conflicting roles in metastasis, leaving its role undefined. In breast cancer LCN2 was shown in previous studies to both inhibit or promote metastasis. Previous studies the Pena laboratory showed that increasing the serum levels of LCN2 caused a significantly increase in liver metastasis of the poorly metastatic MC-38 colon cancer cell line. In this study, we examined the ability of LCN2 to promote metastasis of colon and other cancers to …

Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells, Dasha E. Kenlan, Piotr G. Rychahou, Vitaliy M. Sviripa, Heidi L. Weiss, Chunming Liu, David S. Watt, B. Mark Evers

Markey Cancer Center Faculty Publications

Colorectal cancer is the second-leading cause of cancer-related mortality in the United States. More than 50% of patients with colorectal cancer will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on colorectal cancer metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell-cycle progression and subsequent cellular proliferation. In addition, we demonstrated …

The Role Of Metastasis Suppressor Cd82 In The Deactivation Of The C-Met Signaling Pathway In Prostate Cancer, Katie L. Uhl

Masters Theses

BACKGROUND AND PURPOSE: Prostate cancer is the second leading cause of cancer deaths among men in the United States. Metastasis plays a major role in patient prognosis and treatment options. One of the factors that influences metastasis is the activation of the c-Met signaling pathway. Activation of the growth factor c-Met results in cytoskeletal rearrangement, migration, and invasion. Previous studies have shown CD82 to act as an active metastatic suppressor in normal, healthy cells and is downregulated in various forms of cancer. When CD82 is re-expressed in cancer cells, the cells no longer express metastatic characteristics. The purpose of this …

Fibronectin: How Its Aberrant Expression In Tumors May Improve Therapeutic Targeting, Jennifer Peyling Wang, Abigail Hielscher

PCOM Scholarly Works

Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis. The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance. In particular, this review will focus on the interactions between cell receptor ligands and fibronectin and how this interaction influences downstream signaling events that aid tumor progression. This review will further discuss the possible implications of therapeutic drugs directed against fibronectin and/or cellular interactions with fibronectin and will additionally discuss novel approaches …

Dub3 Inhibition Suppresses Breast Cancer Invasion And Metastasis By Promoting Snail1 Degradation, Yadi Wu, Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana L. Napier, Qiuying Shi, Jiong Deng, B. Mark Evers, Binhua P. Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. …

Oral Melanoma: Relevance To The Dental Team Members, Yeshwant B. Rawal, Thomas B. Dodson, Harbinder S. Bal

School of Dentistry Faculty Research and Publications

Background and Overview

Oral melanomas vary in color and morphology and resemble myriad other reactive, benign, or malignant conditions. The authors describe a case report of a patient with a primary oral melanoma that presented as a nonspecific ulcer, which showed nodal metastasis during resection.

Case Description

A 64-year-old man who was examined by his periodontist to assess implant healing had a reddish-purple ulcer of the maxillary mucosa of 3 to 4 weeks duration. The implant was placed 19 weeks earlier in the mandible. The provisional diagnosis was that this ulcer was a traumatic or inflammatory lesion. The clinician biopsied …

Androgen Receptor-Dependent And -Independent Mechanisms Driving Prostate Cancer Progression: Opportunities For Therapeutic Targeting From Multiple Angles., David T. Hoang, Kenneth A. Iczkowski, Deepak Kilari, William See, Marja T. Nevalainen

Student Papers, Posters & Projects

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC …

Is Necitumumab An Effective Addition To Traditional Chemotherapeutic Regiments When Treating Stage Iv Lung And Colon Cancer?, J. Ross Hosford

PCOM Physician Assistant Studies Student Scholarship

Objective: The objective of this selective EBM review is to determine whether or not Necitumumab is an effective add on treatment to traditional chemotherapy regimes when treating stage IV lung or colon cancer.

Study Designs: Review of two open label, randomized, controlled phase III trials and one single arm multicenter phase II study.

Outcomes Measured: Objective tumor response rate was measured for patients with colon cancer. Overall survival rate and length of survival were measured for patients with lung cancer. This was measured in Kapler Meier Methodology.

Results: For two trials the addition of Necitumumab improved …

The Role Of Adipocytes And Osteocytes In Multiple Myeloma Progression, Timothy Nathan Trotter

All ETDs from UAB

Multiple myeloma (MM) is a hematological malignancy of plasma cells that is intrinsically tied to the bone marrow (BM). Many cells in the BM microenvironment have been studied in MM, yet there is still much progress to be made. Recent work has revealed two new potential cellular targets in MM: adipocytes and osteocytes. Both are endocrine cells and secrete many molecules that regulate other cells proximally and systemically. Our lab previously showed that MM cells shift osteoblast precursor cells towards adipogenesis through soluble molecules alone. Recent findings also revealed that osteocyte apoptosis is enhanced in MM patients compared to healthy …

Elucidating The Physiologic And Prognostic Significance Of N-Myc And Stat Interactor Using Models Of Mammary Development And Metastasis, Hawley Christine Pruitt

All ETDs from UAB

Distant metastasis of breast carcinoma reduces the five year survival rate of patients from 90% to a dismal 25%. Although the metastatic cascade has been extensively studied for decades, players that influence the progression of metastatic disease remain elusive. N-MYC and STAT Interactor (NMI) is a gene previously demonstrated by Devine et. al. to be downregulated with metastatic progression of breast cancer. However, due to the lack of a relevant genetic model, details of biological consequence of the loss of expression of this gene were unknown. We have constructed and characterized a mammary specific Nmi knock out mouse to elucidate …